The proposed work builds on the previously funded research project entitled Role and regulation of the human DEK oncogene. The original application was focused on the role of DEK in HPV positive cervical cancer cells, based on the observation that DEK was up-regulated by the high risk HPV E7 oncogene. We and others subsequently demonstrated that DEK is controlled by E2F/Rb pathways and thus also widely over-expressed in HPV negative cancers. DEK had been suspected to carry oncogenic activities since the early 1990s. In the past several years, we were able to prove such activities for the first time using organotypic epithelial raft cultures and classical keratinocyte transformation assays. Furthermore, we reported a new DEK knockout mouse model which was partially resistant to the development of chemically induced skin papillomas. Herein we propose to investigate the molecular role of DEK in head and neck squamous cell carcinoma (HNSCCs), which can be positive or negative for HPV in cancer patients. In Aim 1, we will carry out DEK loss and gain of function studies in mice to determine the requirement and sufficiency for HNSCC development. In Aim 2, we will investigate newly identified DEK activities in the regulation of b-catenin signaling, EMT, cellular invasion and self-renewal. These experiments will be performed in primary human HNSCC cells. In Aim 3, we will carry out structure-function studies to map tumor-associated DEK domains and to identify nuclear DEK-interacting factors. The results will provide an important first step in advancing our understanding of molecular networks by which this versatile chromatin topology regulator activates oncogenic signaling and phenotypes in human cells (Aim 2) and HNSCC development in mice (Aim 1).